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Comparative study of carvedilol and quinidine for inhibiting hKv4.3 channel stably expressed in HEK 293 cells
- Source :
- European journal of pharmacology. 853
- Publication Year :
- 2018
-
Abstract
- The inhibition of transient outward potassium current (Ito) is the major ionic mechanism for quinidine to treat Brugada syndrome; however, quinidine is inaccessible in many countries. The present study compared the inhibitory effect of the nonselective β-adrenergic blocker carvedilol with quinidine on human Kv4.3 (hKv4.3, encoding for Ito) channel and action potential notch using a whole-cell patch technique in HEK 293 cell line expressing K C N D 3 as well as in ventricular epicardial myocytes of rabbit hearts. It was found that carvedilol and quinidine inhibited hKv4.3 current in a concentration-dependent manner. The IC50 of carvedilol was 1.2 μM for inhibiting hKv4.3 charge area, while the IC50 of quinidine was 2.9 μM (0.2 Hz). Both carvedilol and quinidine showed typical o p e n channel blocking properties (i.e. decreasing the time to peak of activation and increasing the inactivation of hKv4.3), negatively shifted the V1/2 of activation and inactivation, and slowed the recovery from inactivation of the channel. Although carvedilol had weaker in use- and rate-dependent inhibition of hKv4.3 peak current than quinidine, its reduction of the charge area was more than quinidine at all frequencies (0.2–3.3 Hz). Moreover, the inhibitory effect of carvedilol on action potential notch was greater than quinidine. These results provide the novel information that carvedilol, like quinidine, significantly inhibits hKv4.3 and action potential notch, suggesting that carvedilol is likely an alternative drug for preventing malignant ventricular arrhythmias in patients with Brugada syndrome in countries where quinidine is unavailable.
- Subjects :
- 0301 basic medicine
Quinidine
Male
Heart Ventricles
Action Potentials
Gene Expression
Pharmacology
03 medical and health sciences
Inhibitory Concentration 50
0302 clinical medicine
medicine
Potassium Channel Blockers
Myocyte
Animals
Humans
In patient
Myocytes, Cardiac
IC50
Carvedilol
Brugada syndrome
Chemistry
Protein Stability
HEK 293 cells
Peak current
medicine.disease
Kinetics
030104 developmental biology
HEK293 Cells
Shal Potassium Channels
Rabbits
Ion Channel Gating
030217 neurology & neurosurgery
medicine.drug
Subjects
Details
- ISSN :
- 18790712
- Volume :
- 853
- Database :
- OpenAIRE
- Journal :
- European journal of pharmacology
- Accession number :
- edsair.doi.dedup.....02ff9a36b3ef969ce73f181153c9d6c8